Tuesday, October 17, 2017
Project co-funded by the European Commission in the framework of the 2nd Health Programme
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A.7.2.1. General

1. Quality control should be extended to sampling, specifications and testing, as well as the organisation, documentation and release procedures that ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor tissues and cells released for sale or supply, until their quality has been judged to be satisfactory.

2. The basic requirements of quality control are that:

a)    Adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing of starting materials, packaging materials, tissues and cells in all their phases, and where appropriate for monitoring environmental conditions;

b)    Samples of starting materials, packaging materials, tissues and cells in all their phases are taken by personnel and by methods approved by quality control;

c)     Test methods are validated;

d)    Manufacturer’s Certificate of Analysis may be accepted as adequate release criteria for commercial materials on the basis of risk assessment.  Self-made starting materials must be tested;

e)     Records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated;

f)      Records are made of the results of inspection and that testing of materials, tissues and cells in all their phases are formally assessed against specification.  Tissues and cells assessment includes a review and evaluation of relevant processing documentation and an assessment of deviations from specified procedures;

g)    No tissue / cells are released for sale or supply prior to certification by a responsible person.[1]


A.7.2.2. Documentation

1. Laboratory documentation should be consistent with the following principles.  An important part of this documentation deals with quality control and the following details should be readily available to the Quality Control Department:

a)    Specifications;

b)    Sampling procedures;

c)     Testing procedures and records (including analytical worksheets and/or laboratory notebooks);

d)    Analytical reports and/or certificates;

e)     Data from environmental monitoring, where required;

f)      Validation records of test methods, where applicable;

g)    Procedures for and records of the calibration of instruments and maintenance of equipment.[2]

2. Any quality control documentation relating to tissues / cells should be retained for at least 30 years after their clinical use.

3. For some kinds of data (e.g. analytical tests results, environmental controls, data included in product/process quality reviews), it is recommended that records are kept in a manner permitting trend evaluation.

4. In addition to the information which is part of the tissues / cells record, other original data such as laboratory notebooks and / or records should be retained and readily available.[3]

A.7.2.3. Sampling

1. The sample taking should be done in accordance with approved written procedures that describe:

a)    Method of sampling;

b)    Equipment to be used;

c)     Amount of the sample to be taken;

d)    Instructions for any required sub-division of the sample;

e)     Type and condition of the sample container to be used;

f)      Identification of containers sampled;

g)    Any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials;

h)    Storage conditions’

i)      Instructions for the cleaning and storage of sampling equipment.

2. Reference samples should be representative of the tissue / cells or materials from which they are taken.  Other samples may also be taken to monitor the most stressed part of a process (e.g. beginning or end of a process).

3. Sample containers should bear a label indicating the contents, with the tissue / cells code / batch number, the date of sampling and the containers from which samples have been drawn.

4. Further guidance on reference and retention samples is given in the following sections.[4]

A.7.2.4. Testing

1. Analytical methods should be validated.  All testing operations should be carried out according to the approved methods.

2. The results obtained should be recorded and checked to make sure that they are consistent with each other.  Any calculations should be critically examined.

3. The tests performed should be recorded and the records should include at least the following data:

a)    Name of the material or tissue/cells and, where applicable, presentation;

b)    Code/batch number and, where appropriate, the processor and/or supplier;

c)     References to the relevant specifications and testing procedures;

d)    Test results, including observations and calculations, and reference to any certificates of analysis;

e)     Dates of testing;

f)      Initials of the persons who performed the testing;

g)    Initials of the persons who verified the testing and the calculations, where appropriate;

h)    A clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person.

4. All the in-process controls, including those made in the processing area by processing personnel, should be performed according to methods approved by Quality Control and the results recorded.[5]

5. Special attention should be given to the quality of laboratory reagents, volumetric glassware and solutions, reference standards and culture media.  They should be prepared in accordance with written procedures.

6. Laboratory reagents intended for prolonged use should be marked with the preparation date and the signature of the person who prepared them.  The expiry date of unstable reagents and culture media should be indicated on the label, together with specific storage conditions.  In addition, for volumetric solutions, the last date of standardisation and the last current factor should be indicated.

7. Where necessary, the date of receipt of any substance used for testing operations (e.g. reagents and reference standards) should be indicated on the container.  Instructions for use and storage should be followed.  In certain cases it may be necessary to carry out an identification test and/or other testing of reagent materials upon receipt or before use.[6]

A.7.2.5. Stability Monitoring

1. After distribution, the stability of the tissues and cells should be monitored according to a continuous appropriate programme that will permit the detection of any stability issue (e.g. integrity, elasticity, changes in levels of impurities or dissolution profile) associated with the presentation in the shipping package.[7]

2. Due to the variability of the tissues and cells, requirements for stability monitoring should be defined on a case-by-case basis.

3. A documented, on-going testing programme should be designed to monitor the stability characteristics of tissues and cells.  The results should be used to confirm appropriate storage conditions and retest dates or expiry dates.

4. The purpose of the on-going stability programme is to monitor the tissues/cells over its shelf life and to determine that the tissue/cells remains, and can be expected to remain, within specifications under the labelled storage conditions.[8]

5. Normally three representative tissues / three cells batches should be placed on the stability monitoring programme to confirm the retest or expiry date.

6. Stability testing should be suitable to their shelf-life / retest period and / or batch size.  For tissues / cells with a shelf-life of several days a scientific based programme needs to be implemented.  For tissues / cells with shelf-lives of at least six months, ICH recommendations should be followed, if the amount of sampled material allows.

7. Where relevant, a stability monitoring programme should be put in place and retain samples in sufficient quantity to permit further examination at a later stage.

8. The protocol for an on-going stability programme should extend to the end of the shelf life period and should include, but not be limited to, the following parameters:

a)    Number of batch(es) per strength and different batch sizes, if applicable;

b)    Relevant physical, chemical, microbiological and biological test methods;

c)     Acceptance criteria;

d)    Reference to test methods;

e)     Description of the container closure system(s);

f)      Testing intervals (time points);

g)    Description of the conditions of storage (standardised ICH conditions for long term);

h)    Testing, consistent with the product labelling, should be used);

i)      Other applicable parameters specific to the tissues/cells.

10. A summary of all the data generated, including any interim conclusions on the programme, should be written and maintained.  This summary should be subjected to periodic review.[9]

A.7.2.6. Expiry Date

1. The expiry or retest date should come from formal stability studies data performed on at least three representative tissues or three cells batches.  The tissues and cells should be processed to a minimum of pilot scale and using a method of processing that simulates the final process.

2. A representative sample should be taken for the purpose of performing a retest.

[1] EU Good Manufacturing Practices Guidelines

[2] EU Good Manufacturing Practices Guidelines

[3] EU Good Manufacturing Practices Guidelines

[4] EU Good Manufacturing Practices Guidelines

[5] EU Good Manufacturing Practices Guidelines

[6] EU Good Manufacturing Practices Guidelines

[7] EU Good Manufacturing Practices Guidelines

[8] EU Good Manufacturing Practices Guidelines

[9] EU Good Manufacturing Practices Guidelines

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